t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway

An Erratum to this article was published on 01 March 2003


Truncation of Notch1 has been shown to cause a subtype of acute leukemia1, and activation of Notch4 has been associated with mammary and salivary gland carcinomas of mice2. Here we identify a new mechanism for disrupting Notch signaling in human tumorigenesis, characterized by altered function of a new ortholog of the Drosophila melanogaster Notch co-activator molecule Mastermind. We cloned the t(11;19) translocation that underlies the most common type of human malignant salivary gland tumor. This rearrangement fuses exon 1 from a novel gene of unknown function at 19p13, termed mucoepidermoid carcinoma translocated 1 (MECT1), with exons 2–5 of a novel member of the Mastermind-like gene family (MAML2) at 11q21 (ref. 3). Similar to D. melanogaster Mastermind and MAML1 (refs. 4,5), full-length MAML2 functioned as a CSL (CBF-1, suppressor of hairless and Lag-1)-dependent transcriptional co-activator for ligand-stimulated Notch. In contrast, MECT1–MAML2 activated transcription of the Notch target gene HES1 independently of both Notch ligand and CSL binding sites. MECT1–MAML2 induced foci formation in RK3E epithelial cells, confirming a biological effect for the fusion product. These data suggest a new mechanism to disrupt the function of a Notch co-activator in a common type of malignant salivary gland tumor.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: t(11;19) rearrangement creates a MECT1–MAML2 fusion transcript.
Figure 2: MECT1–MAML2 co-localizes with ICN1, is deficient in its ability to form a ternary complex with CSL and retains a TAD.
Figure 3: MECT1–MAML2 activation is independent of Jagged2 stimulation and CSL binding sites and shows narrow promoter specificity.
Figure 4: Effect of MECT1–MAML2, MECT1–MAML1 and MECT1–VP16 on an artificial promoter containing four tandem CSL binding sites.
Figure 5: Induction of Notch target genes by the MECT1–MAML2 product in vivo.

Accession codes




  1. 1

    Ellisen, L.W. et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66, 649–661 (1991).

    CAS  Article  Google Scholar 

  2. 2

    Jhappan, C. et al. Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev. 6, 345–355 (1992).

    CAS  Article  Google Scholar 

  3. 3

    Wu, L., Sun, T., Kobayashi, K., Gao, P. & Griffin, J.D. Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors. Mol. Cell. Biol. 22, 7688–7700 (2002).

    CAS  Article  Google Scholar 

  4. 4

    Artavanis-Tsakonas, S., Matsuno, K. & Fortini, M.E. Notch signaling. Science 268, 225–232 (1995).

    CAS  Article  Google Scholar 

  5. 5

    Wu, L. et al. MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat. Genet. 26, 484–489 (2000).

    CAS  Article  Google Scholar 

  6. 6

    Johansson, M. et al. Translocation 11;19 in a mucoepidermoid tumor of the lung. Cancer Genet. Cytogenet. 80, 85–86 (1995).

    CAS  Article  Google Scholar 

  7. 7

    Horsman, D.E., Berean, K. & Durham, J.S. Translocation (11;19)(q21;p13.1) in mucoepidermoid carcinoma of salivary gland. Cancer Genet. Cytogenet. 80, 165–166 (1995).

    CAS  Article  Google Scholar 

  8. 8

    El-Naggar, A.K., Lovell, M., Killary, A.M., Clayman, G.L. & Batsakis, J.G. A mucoepidermoid carcinoma of minor salivary gland with t(11;19)(q21;p13.1) as the only karyotypic abnormality. Cancer Genet. Cytogenet. 87, 29–33 (1996).

    CAS  Article  Google Scholar 

  9. 9

    Dahlenfors, R., Wedell, B., Rundrantz, H. & Mark, J. Translocation(11;19)(q14–21;p12) in a parotid mucoepidermoid carcinoma of a child. Cancer Genet. Cytogenet. 79, 188 (1995).

  10. 10

    Dahlenfors, R., Lindahl, L. & Mark, J. A fourth minor salivary gland mucoepidermoid carcinoma with 11q14–21 and 19p12 rearrangements. Hereditas 120, 287–288 (1994).

    CAS  Article  Google Scholar 

  11. 11

    Mitelman, F. Recurrent chromosome aberrations in cancer. Mutat. Res. 462, 247–253 (2000).

    CAS  Article  Google Scholar 

  12. 12

    Xu, T., Rebay, I., Fleming, R.J., Scottgale, T.N. & Artavanis-Tsakonas, S. The Notch locus and the genetic circuitry involved in early Drosophila neurogenesis. Genes Dev. 4, 464–475 (1990).

    CAS  Article  Google Scholar 

  13. 13

    Jarriault, S. et al. Signalling downstream of activated mammalian Notch. Nature 377, 355–358 (1995).

    CAS  Article  Google Scholar 

  14. 14

    Petcherski, A.G. & Kimble, J. Mastermind is a putative activator for Notch. Curr. Biol. 10, R471–R473 (2000).

    CAS  Article  Google Scholar 

  15. 15

    Kojika, S. & Griffin, J.D. Notch receptors and hematopoiesis. Exp. Hematol. 29, 1041–1052 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Dumont, E. et al. Neoplastic transformation by Notch is independent of transcriptional activation by RBP-J signalling. Oncogene 19, 556–561 (2000).

    CAS  Article  Google Scholar 

  17. 17

    Capobianco, A.J., Zagouras, P., Blaumueller, C.M., Artavanis-Tsakonas, S. & Bishop, J.M. Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and NOTCH2. Mol. Cell. Biol. 17, 6265–6273 (1997).

    CAS  Article  Google Scholar 

  18. 18

    Petcherski, A.G. & Kimble, J. LAG-3 is a putative transcriptional activator in the C. elegans Notch pathway. Nature 405, 364–368 (2000).

    CAS  Article  Google Scholar 

  19. 19

    Wolfe, M.S. γ-Secretase inhibitors as molecular probes of presenilin function. J. Mol. Neurosci. 17, 199–204 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Hsieh, J.J. et al. Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein–Barr virus EBNA2. Mol. Cell. Biol. 16, 952–959 (1996).

    CAS  Article  Google Scholar 

  21. 21

    Wallberg, A.E., Pedersen, K., Lendahl, U. & Roeder, R.G. p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by Notch intracellular domains in vitro. Mol. Cell. Biol. 22, 7812–7819 (2002).

    CAS  Article  Google Scholar 

  22. 22

    Fryer, C.J., Lamar, E., Turbachova, I., Kintner, C. & Jones, K.A. Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex. Genes Dev. 16, 1397–1411 (2002).

    CAS  Article  Google Scholar 

  23. 23

    Tonon, G. et al. Spectral karyotyping combined with locus-specific FISH simultaneously defines genes and chromosomes involved in chromosomal translocations. Genes Chromosom. Cancer 27, 418–423 (2000).

    CAS  Article  Google Scholar 

  24. 24

    Greenberg, R.A. et al. Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene 18, 1219–1226 (1999).

    CAS  Article  Google Scholar 

  25. 25

    Tang, H.Y. et al. Constitutive expression of the cyclin-dependent kinase inhibitor p21 is transcriptionally regulated by the tumor-suppressor protein p53. J. Biol. Chem. 273, 29156–29163 (1998).

    CAS  Article  Google Scholar 

  26. 26

    Kwon, T.K., Nagel, J.E., Buchholz, M.A. & Nordin, A.A. Characterization of the murine cyclin-dependent kinase inhibitor gene p27Kip1. Gene 180, 113–120 (1996).

    CAS  Article  Google Scholar 

  27. 27

    Beatus, P., Lundkvist, J., Oberg, C. & Lendahl, U. The notch 3 intracellular domain represses notch 1-mediated activation through Hairy/Enhancer of split (HES) promoters. Development 126, 3925–3935 (1999).

    CAS  Google Scholar 

  28. 28

    Bessho, Y., Miyoshi, G., Sakata, R. & Kageyama, R. Hes7: a bHLH-type repressor gene regulated by Notch and expressed in the presomitic mesoderm. Genes Cells 6, 175–185 (2001).

    CAS  Article  Google Scholar 

  29. 29

    Winter, E., Yamamoto, F., Almoguera, C. & Perucho, M. A method to detect and characterize point mutations in transcribed genes: amplification and overexpression of the mutant c-Ki-ras allele in human tumor cells. Proc. Natl. Acad. Sci. USA 82, 7575–7579 (1985).

    CAS  Article  Google Scholar 

  30. 30

    Ruppert, J.M., Vogelstein, B. & Kinzler, K.W. The zinc-finger protein GLI transforms primary cells in cooperation with adenovirus E1A. Mol. Cell. Biol. 11, 1724–1728 (1991).

    CAS  Article  Google Scholar 

Download references


We are grateful to M. Kuehl, P. Aplan and T. Ried for helpful suggestions; P. Gao and J. Liu for their help; B. Baum for providing the HSY cells; M. Wolfe for providing the γ-secretase inhibitor; and A. Capobianco for advice on the RK3E assay. We acknowledge partial support by an American Society of Hematology Scholar Award and a General Motors Cancer Research Scholar Award (L.W.).

Author information



Corresponding author

Correspondence to Frederic J. Kaye.

Ethics declarations

Competing interests

A patent application has been filed (by F.J.K. and G.T.) for the molecular diagnosis of mucoepidermoid carcinoma.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Tonon, G., Modi, S., Wu, L. et al. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 33, 208–213 (2003). https://doi.org/10.1038/ng1083

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing